ABCMdb

ABCC8 p.Arg248Cys

Predicted by SNAP2:	A: N (87%), C: N (61%), D: N (72%), E: N (72%), F: N (57%), G: N (82%), H: N (72%), I: N (87%), K: N (93%), L: N (78%), M: N (72%), N: N (93%), P: N (82%), Q: N (87%), S: N (93%), T: N (93%), V: N (87%), W: D (59%), Y: N (53%),
Predicted by PROVEAN:	A: N, C: D, D: N, E: N, F: D, G: N, H: N, I: D, K: N, L: D, M: N, N: N, P: N, Q: N, S: N, T: N, V: D, W: D, Y: D,

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[hide] Fibroblast growth factor receptor 3 mutations prom... J Biol Chem. 1998 May 22;273(21):13007-14. Legeai-Mallet L, Benoist-Lasselin C, Delezoide AL, Munnich A, Bonaventure J
Fibroblast growth factor receptor 3 mutations promote apoptosis but do not alter chondrocyte proliferation in thanatophoric dysplasia.
J Biol Chem. 1998 May 22;273(21):13007-14., [PMID:9582336]

Abstract [show]
Thanatophoric dysplasia (TD) is a lethal skeletal disorder caused by recurrent mutations in the fibroblast growth factor receptor 3 (FGFR 3) gene. The mitogenic response of fetal TD I chondrocytes in primary cultures upon stimulation by either FGF 2 or FGF 9 did not significantly differ from controls. Although the levels of FGFR 3 mRNAs in cultured TD chondrocytes were similar to controls, an abundant immunoreactive material was observed at the perinuclear level using an anti-FGFR 3 antibody in TD cells. Transduction signaling via the mitogen-activated protein kinase pathway was assessed by measuring extracellular signal-regulated kinase activity (ERK 1 and ERK 2). Early ERKs activation following FGF 9 supplementation was observed in TD chondrocytes (2 min) as compared with controls (5 min) but no signal was detected in the absence of ligand. By contrast ligand-independent activation of the STAT signaling pathway was demonstrated in cultured TD cells and confirmed by immunodetection of Stat 1 in the nuclei of hypertrophic TD chondrocytes. Moreover, the presence of an increased number of apoptotic chondrocytes in TD fetuses was associated with a higher expression of Bax and the simultaneous decrease of Bcl-2 levels. Taken together, these results indicate that FGFR 3 mutations in TD I fetuses do not hamper chondrocyte proliferation but rather alter their differentiation by triggering premature apoptosis through activation of the STAT signaling pathway.

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No. Sentence Comment
84 Mutant genotypes included the R248C (8/14), S249C (2/14), J807G (1/14), and Y373C (3/14) mutations (Table I). Login to comment

[hide] Abnormal FGFR 3 expression in cartilage of thanato... Hum Mol Genet. 1997 Oct;6(11):1899-906. Delezoide AL, Lasselin-Benoist C, Legeai-Mallet L, Brice P, Senee V, Yayon A, Munnich A, Vekemans M, Bonaventure J
Abnormal FGFR 3 expression in cartilage of thanatophoric dysplasia fetuses.
Hum Mol Genet. 1997 Oct;6(11):1899-906., [PMID:9302269]

Abstract [show]
Thanatophoric dysplasia (TD), the commonest lethal skeletal dysplasia in humans, is accounted for by recurrent mutations in the fibroblast growth factor receptor 3 gene (FGFR 3), causing its constitutive activation in vitro. Taking advantage of medical abortion of 18 TD fetuses, cartilage sections were studied for FGFR 3 gene expression by in situ hybridization and immunohistochemistry. Specific antibodies revealed high amounts of FGFR 3 in cartilage of TD fetuses with no increased level of the corresponding mRNA. The specific signal was mainly detected in the nucleus of proliferative and hypertrophic chondrocytes. Based on this observation and the abnormal expression of collagen type X in hypertrophic TD chondrocytes, we suggest that constitutive activation of the receptor through formation of a stable dimer increases its stability and promotes its translocation into the nucleus, where it might interfere with terminal chondrocyte differentiation.

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63 Gestational age (weeks) FGFR 3 mutation In situ hybridization Immunohistochemistry demineralized non demineralized 1 17 Y373C - + - 2 26 J807G - + - 3 27 R248C - + - 4 23 S249C - + - 5 21 J807C - + - 6 19 Y373C + - + 7 27 R248C + + + 8 26 R248C + + + 9 19 R248C + + + 10 24 S249C + + + 11 16 J807R - - + 12 24 Y373C - + - 13 27 n.a. - + - 14 21 n.a. - + - 15 23 n.a. - + - 16 24 Y373C - + - 17 25 R248C - + - 18 21 ? Login to comment
74 Mutant genotypes included the R248C (5/18), S249C (2/18), Y373C (4/18) and stop codon mutations (3/18) (Table 1). Login to comment